Synthesis of highly fluorinated amines for use in polymers and biomaterials

ABSTRACT

A method for forming a fluorinated compound includes a step of forming a sulfonate ester of a polyethylene glycol. The sulfonate ester is then reacted with a fluorinated diol in the presence of a base such that the polyethylene glycol is attached to one of the hydroxyl groups in the fluorinated diol. The other hydroxyl group in the fluorinated diol is reacted is converted into a leaving group and reacted with an number of nucleophiles. Complexes of the fluorinated compounds that as useful in Magnetic Resonance Imaging are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation in part of PCT Patent Application No.PCT/US10/62104 filed Dec. 24, 2010, which claims the benefit of U.S.provisional Application No. 61/290,053 filed Dec. 24, 2009, the entiredisclosures of which are incorporated herein by reference. Thisapplication also claims the benefit of U.S. provisional Application No.61/504,883 filed Jul. 6, 2011, the entire disclosure of which isincorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

The invention was made with Government support under Contract No.DBI-0821671. The Government has certain rights to the invention.

FIELD OF THE INVENTION

In at least one aspect, the present invention relates methods andapplication of highly fluorinated compounds.

BACKGROUND OF THE INVENTION

Fluorinated amphiphiles are an important class of compounds because oftheir tendency to self-assemble into nanostructures such as monolayers,micelles, or vesicles, in a fashion distinct from theirhydrocarbon-based counterparts. Particularly, amine andguanidine-terminated molecules in this class can potentially decoratephosphate-rich biomolecules through selective non-covalent interactionssuch as hydrogen bonding.

While syntheses of several highly fluorinated amphiphiles or surfactantshave been reported, amine- and guanidine-functionalized fluorocarbonsremain largely under-addressed despite the potential synthetic utilityof nitrogen-containing groups as functionalization handles andbiochemical tools. The known synthetic routes to highly fluorinatedamines have drawbacks: for example, highly fluorinated amines can beprepared from routes such as fluoroalkylation of ammonia with an alkylchloride, hydrogenation of fluoro-organic azides, and the Gabrielsynthesis, with the latter two involving high-temperature displacementof fluoroalkyl tosylates. These methods are of limited scope or involveharsh conditions incompatible with some biologically relevantsubstrates.

Accordingly, there is a need for improved methods of making amphiphilesthat are useful for biochemical applications.

SUMMARY OF THE INVENTION

The present invention solves one or more problems of the prior art byproviding in at least one embodiment a method for forming a fluorinatedcompound is provided. The method includes a step of tosylating acompound having formula 1 to form a compound having formula 2:

The compound having formula (2) is reacted with a compound havingformula (3) to form a compound having formula (4):

The hydroxyl group bonded to the carbon labeled “1” of the compoundhaving formula (4) is converted to a leaving group to form the compoundhaving formula (5):

The compound with the leaving group is reacted with a nucleophile to thecompound having formula (6):

In formulae 1-6, Le is a leaving group, R is a C₁₋₆ alkyl, m is aninteger from 3 to 7, n is an integer from 3 to 10, and Nu₁ is a portionof the nucleophile that bonds to the carbon atom labeled 1.

In another embodiment, a complex having formula (15) or (16) isprovided:

wherein:

m is an integer from 3 to 7;

n is an integer from 3 to 10;

R₁ is a C₈₋₃₀ hydrocarbon group, a functionalized C₈₋₃₀ hydrocarbongroup such that R₁ is fully saturated or includes 1 to 4 carbon tocarbon double bonds or 1 to 4 carbon to carbon triple bonds orcombinations thereof;

R₂ is H, a C₈₋₃₀ hydrocarbon group, a functionalized C₈₋₃₀ hydrocarbongroup such that R₁ is fully saturated or includes 1 to 4 carbon tocarbon double bonds or 1 to 4 carbon to carbon triple bonds; and

R₃ and R₄ are each independently a C₈₋₃₀ hydrocarbon group.

In still another embodiment, a method of making a fluorinated compoundis provided. The method includes a step of converting a compound havingformula (18) to a compound having formula (19):

The compound having formula (18) is converted to a compound havingformula 20:

wherein is an integer from 3 to 10 and Nu₁ is a portion of a nucleophilethat bonds to the compound having formula (18).

BRIEF DESCRIPTION OF THE DRAWINGS

Exemplary embodiments of the present invention will become more fullyunderstood from the detailed description and the accompanying drawings,wherein:

FIG. 1 provides a synthetic scheme of the synthesis of fluorinatedcompounds;

FIG. 2 provides a synthetic scheme reacting the compound having formula(5) with a nucleophile;

FIG. 3 provides a synthetic scheme for converting the compound havingformula (10) to a compound having formula (11):

FIG. 4 provides a synthetic scheme in which the compound having formula(5) is reacted with N₃ ⁻;

FIG. 5 provides a synthetic scheme for forming complexes (15) and (16);

FIG. 6 provides a synthetic scheme for bi-directional functionalizationof fluorinated diols;

FIG. 7 provides a synthetic scheme for fluorinated bis(sulfonic) Ester30.

FIGS. 8A-B provide a synthetic scheme for making fluorous amphiphiles;

FIG. 9 provides a synthetic scheme for making fluorous amphiphiles;

FIG. 10 depicts the binding of guanidinium to phophonate and depicts aurea complexed to a phosphonate; and

FIGS. 11A-D provide ³¹P NMR plots showing the interaction between anamphiphile and MePO₃K₂.

DESCRIPTION OF THE INVENTION

Reference will now be made in detail to presently preferredcompositions, embodiments and methods of the present invention, whichconstitute the best modes of practicing the invention presently known tothe inventors. The Figures are not necessarily to scale. However, it isto be understood that the disclosed embodiments are merely exemplary ofthe invention that may be embodied in various and alternative forms.Therefore, specific details disclosed herein are not to be interpretedas limiting, but merely as a representative basis for any aspect of theinvention and/or as a representative basis for teaching one skilled inthe art to variously employ the present invention.

Except in the examples, or where otherwise expressly indicated, allnumerical quantities in this description indicating amounts of materialor conditions of reaction and/or use are to be understood as modified bythe word “about” in describing the broadest scope of the invention.Practice within the numerical limits stated is generally preferred.Also, unless expressly stated to the contrary: percent, “parts of,” andratio values are by weight; the description of a group or class ofmaterials as suitable or preferred for a given purpose in connectionwith the invention implies that mixtures of any two or more of themembers of the group or class are equally suitable or preferred;description of constituents in chemical terms refers to the constituentsat the time of addition to any combination specified in the description,and does not necessarily preclude chemical interactions among theconstituents of a mixture once mixed; the first definition of an acronymor other abbreviation applies to all subsequent uses herein of the sameabbreviation and applies mutatis mutandis to normal grammaticalvariations of the initially defined abbreviation; and, unless expresslystated to the contrary, measurement of a property is determined by thesame technique as previously or later referenced for the same property.

It is also to be understood that this invention is not limited to thespecific embodiments and methods described below, as specific componentsand/or conditions may, of course, vary. Furthermore, the terminologyused herein is used only for the purpose of describing particularembodiments of the present invention and is not intended to be limitingin any way.

It must also be noted that, as used in the specification and theappended claims, the singular form “a,” “an,” and “the” comprise pluralreferents unless the context clearly indicates otherwise. For example,reference to a component in the singular is intended to comprise aplurality of components.

Throughout this application, where publications are referenced, thedisclosures of these publications in their entireties are herebyincorporated by reference into this application to more fully describethe state of the art to which this invention pertains.

ABBREVIATIONS

-   -   “TfO-” or “-OTf” stands for Trifluoromethanesulfonate;    -   “DMF” stands for dimethylformamide;    -   “DCM” stands for dichloromethane;    -   “TEA” stands for triethylamine;    -   “rt” stands for room temperature;    -   “Et” stands for ethyl;    -   “i-Pr” stands for isopropyl; and    -   “hrs” stands for hours.

In an embodiment of the present invention, a method for forming afluorinated compound is provided. FIG. 1 provides a synthetic scheme ofthe synthesis of this embodiment and related variations. The methodincludes a step of converting the hydroxyl group of the compound havingformula (1) to a sulfonate ester. For example, the compound havingformula 1 is toslyated to form a sulfonate ester such as a compoundhaving formula 2:

The sulfonate ester (e.g., the compound having formula (2)) is reactedwith a compound having formula (3) to form a compound having formula (4)typically in the presence of a chemical base (e.g., NaH):

The hydroxyl group bonded to the carbon labeled “1” of the compoundhaving formula (4) is converted to a leaving group to form the compoundhaving formula (5):

The compound with the leaving group is reacted with a nucleophile to thecompound having formula (6):

In formulae 1-6, Le is a leaving group, R is a C₁₋₆ alkyl, m is aninteger from 3 to 7, n is an integer from 3 to 10, and Nu₁ is a portionof the nucleophile that bonds to the carbon atom labeled 1.

In a variation, in the step of converting the hydroxyl to a leavinggroup, the compound having formula (4) is reacted withtrifluoromethanesulfonyl chloride to form a compound having formula (7):

With reference to FIG. 2, a synthetic scheme for reacting the compoundhaving formula (5) with a nucleophile is provided. The nucleophile thatis reacted with the compound having formula (5) has the followingformula (8):

to form a compound having formula (9):

In a refinement, the compound having formula (9) is converted to acompound having formula (10):

or the amine protonated derivative thereof represented by formula (10A):

In a refinement, the compound having formula (9) is reacted withhydrazine to form the compound having formula (10) or (10A).

Other nucleophile which may be used in the practice of the presentembodiment include, but are not limited to, halide (Cl⁻, Br⁻, I⁻, F⁻), acompound having formula (11), and the like:

With reference to FIG. 3, the compound having formula (10) is convertedto a compound having formula (12):

(12) or the imine protonated derivative thereof.An example of such a conversion is to react the compound having formula(10) is reacted with a compound having formula (13) to form the compoundhaving formula (12):

With reference to FIG. 4, the compound having formula (5) is reactedwith N₃ ⁻ (i.e., an azide salt) to form a compound having formula (14):

The compound having formula (14) is then converted to the compoundhaving formula (10). As depicted in FIG. 4, the compound having formula(10) is converted to a compound having formula (12).

With reference to FIG. 5, the compound having formula (12) is reactedwith a compound having —PO₃OR₂ ⁻ (phosphonate) or —CO₂ ⁻ (carboxylate)groups to form a complex having formula (15) or (16) respectively:

wherein m is an integer from 3 to 7; n is an integer from 3 to 10; R₁ isa C₈₋₃₀ hydrocarbon group, a functionalized C₈₋₃₀ hydrocarbon group suchthat R₁ is fully saturated or includes 1 to 4 carbon to carbon doublebonds (i.e., an alkenyl group) or 1 to 4 carbon to carbon triple bonds(an alkynyl group) or combinations thereof and R₂ is H, a C₈₋₃₀hydrocarbon group, a functionalized C₈₋₃₀ hydrocarbon group such that R₁is fully saturated or includes 1 to 4 carbon to carbon double bonds or 1to 4 carbon to carbon triple bonds. In a refinement, R₁ and R₂ include 1to 8 herteroatoms such as S, O, or N. Examples of functional groups aregroups including —SH which allows bonding to metals such as gold.Examples of R₁ include the moieties having formula (17A) and (17A):

where the squiggly line intersecting the line represents the point ofattachment of this group, R₃ and R₄ are each independently a C₈₋₃₀hydrocarbon group. In a refinement, R₃ and R₄ are each independently aC₈₋₃₀ alkyl group. In a further refinement, and R₄ are eachindependently a C₈₋₃₀ alkylene group having 1 to 4 carbon to carbondouble bonds or a C₈₋₃₀ alkynyl group having 1 to 4 carbon to carbontriple bonds. It should be appreciated that R₁ which include hydrophobicdomains.

In a particular variation, the complex having formula (15) or (16) ispart of a nanoparticle. Details of such nanoparticles as provided in PCTpatent application no. PCT/US10/62104 filed Feb. 11, 2011; the entiredisclosure of which is hereby incorporated by reference. In arefinement, the complex having formulae (15) or (16) is functionalized(e.g., with a —SH) to be bonded to a metal such as gold. In thisvariation, complex having formulae (15) or (16) act as a hydrophobicshell in the nanoparticles. In another refinement, the nanoparticleincludes a paramagnetic atom such as gadolinium(III) metal.Nanoparticles that include paramagnetic metals are useful for magneticresonance imaging (MRI). Such paramagnetic metals enable rapidrelaxation of the spins in hydrogen atoms in a coordinated watermolecules. This makes the water molecules in the proximity of the metalappear more brilliantly in the MRI image. The relaxation property istransferred to neighboring water molecules by ligand exchange (H₂O forH₂O) and proton transfer from coordinated water to bulk solvent. Thiscontact effect can be attenuated if the metal can be protected frominteracting with its surrounding aqueous environment. In the presentvariation, the complex having formulae (15) or (16) will isolate theparamagnetic atom from surrounding water via the hydrophobic componentof the compound having formula (11). In a typical MRI application, thenanoparticle is introduced into a subject; separating the complex havingformula (11) to expose the PO₃H⁻ groups; and imaging the paramagneticatom by magnetic resonance imaging.

In another embodiment, a method of forming a complex is provided. Themethod includes a step in which a compound having formula (10) in whicha compound having —PO₂OH⁻ or —CO₂ ⁻ groups to form a complex havingformula (15) or (16) respectively:

In a refinement, the complex having formula (15) or (16) is part of ananoparticle which may include a paramagnetic atom such asgadolinium(III). Such a nanoparticle is useful for magnetic resonanceimaging (MRI). In a typical MRI application, the nanoparticle isintroduced into a subject; separating the complex having formula (11) toexpose the PO₃H⁻ groups; and imaging the paramagnetic atom by magneticresonance imaging.

In another embodiment, a complex having formula (15) is provided:

wherein

m is an integer from 3 to 7; and

n is an integer from 3 to 10.

With reference to FIG. 6, another embodiment of making a fluorinatedcompound is provided. The method includes a step of converting acompound having formula (18) to a compound having formula (19):

The compound having formula (19) is then converted to a compound havingformula 20:

In formula 16-17, n is an integer from 3 to 10, and Nu₁ is a portion ofthe nucleophile that bonds to the compound having formula (18). Exampleof suitable nucleophiles include, but are not limited to halide (e.g.,Cl—, Br—, F—, I— with a suitable counter ion such as K⁺, Na⁺ etc),

N₃ ⁻, and the like. Each of these anions are associated with a suitablecounter ion such as K⁺, Na⁺ etc.

The following examples illustrate the various embodiments of the presentinvention. Those skilled in the art will recognize many variations thatare within the spirit of the present invention and scope of the claims.

Fluorous amphiphiles are constructed by attaching a fluorous diol, suchas compound (21), to a poly(ethylene glycol) (PEG) fragment. A generaloutline of this operation is shown in the synthetic scheme of FIGS. 8A-Band 9. Accordingly, a tosylate-functionalized PEG fragment (21) is usedto effect selective mono-alkylation of compound (21) in the presence ofsodium hydride. The resulting PEG-functionalized fluorous alcohol can befurther elaborated. A triflate is installed to mediate furtherfunctionalization, although several sulfonate esters are known totransfer polyfluoroalkyl groups. We presumed that the added reactivityof the triflate would be important to effect efficient displacementreactions. Sulfonation of fluorous alcohols is often carried out indichloromethane, yet sulfonation of compound (25a) in dichloromethanewas relatively slow. A simple change of solvent to tetrahydrofuranaccelerated the rate of the reaction, affording triflate (25a) inexcellent yield. C—N bond formation can be affected by triflatedisplacement with either (i) potassium phthalimide or (ii) sodium azide.Hydrogenation of the azide was more convenient in our hands.

Guanylation of amines (27a-c) is challenging because the proximalfluorine atoms reduce the nucleophilicity of the precursor amine.Nonetheless, successful guanylation is realized with an excess ofguanylpyrazole and Hünig's base. 1H-pyrazole-1-carboximidamide isselected due to its mild guanylation conditions and ease of use.Remarkably, these guanylation reactions proceed to completion despitethe attenuated nucleophilicity of the fluoroalkyl amines. This route canbe generalized to generate homologs of compound (29a) featuringdifferent lengths of the fluorocarbon (Table 1, entries 16-18).

TABLE 1 Synthesis Fluorinated Amphiphiles. Starting Entry MaterialProduct Conditions Yield 1 22 

23 TsCl, pyridine, DCM, −20° C. 94% 2 21a

24a  NaH, dioxane, 90° C. 62% 3 21b

24b NaH, dioxane, 90° C. 51% 4 21c

24c NaH, dioxane, 90° C. 60% 5 24a

25a TfCl, THF, 0° C.-rt,  81%^(a) 6 24b

25b TfCl, THF, 0° C.-rt, 60% 7 24c

25c TfCl, THF, 0° C.-rt,  93%^(b) 8 25a

26 KN(phthal), DMF, 85° C. 84% 9 25a

28a NaN₃, DMF, rt 84% 10  25b

28b NaN₃, DMF, rt >99%  11  25c

28c NaN₃, DMF, rt 87% 12  26 

27a H₂NNH₂, EtOH, 65° C. 93% 13  25a

27a a. NaN₃, DMF, b. H₂ (balloon), Pd/C, rt 70% 14  26b

27b H₂ (balloon), Pd/C, rt 72% 15  25c

27c a. NaN₃, DMF, b. H₂ (balloon), Pd/C, rt 65% 16  27a

29a

92% 17  27b

29b

57% 18  27c

29c

56% ^(a,b)95% conversion.3. Binding of Fluorinated Amphiphiles to a Phosphonic Acid.

Guanidinium binds to phosphonate through a salt bridge that isbuttressed by a bidentate hydrogen bonding system FIG. 10. Thisinteraction is generally stable within a wide range of pH values. Thus,guanidinium-functionalized amphiphiles (29a-c) should form complexeswith phosphonates in aqueous buffer. We show here the interactionbetween amphipile (29a) and MePO₃K₂ using ³¹P NMR, FIGS. 11A-D, whichhas been used as a probe for phosphate binding to several types ofcations. FIG. 11A shows that as compound 29a is added to a solution ofphosphonate, the ³¹P chemical shift of the phosphonate moves onlyslightly, but broadens significantly. This broadening effect is morepronounced as additional compound (29a) is added. The change in theshape of the peak is consistent with reduced tumbling associated withincreased size or reversible association of compound (29a) with MePO₃K₂,which indicates complexation between the guanidinium species and thephosphonate group. By contrast, FIG. 11B shows that in the presence ofHCl, a strong Brønsted acid, protonated MePO₃H₂ remains sharp and shiftsdownfield to 30.4 ppm. Thus, guanidinium compound (29a) is not merelyprotonating the phosphonate in FIG. 11A. Treatment of MePO₃K₂ with NH₄Clresulted in a small downfield shift like HCl, but did not broaden thesignal like compound (29a). Urea is structurally similar to guanidiniumand can potentially complex a phosphonate in a manner similar tocompound (29a) (FIG. 10). In the presence of HCl, similar chemicalbehavior is expected when MePO₃K₂ is treated with urea as when it istreated with compound 29. Interestingly, these peaks do not broaden asis observed with the apparent MePO₃K₂-9a complex (FIG. 11D). Overall,these spectra show that complexes depicted in FIG. 10 methylphosphonateas indicated by NMR properties which different from those of thecorresponding free phosphonate, phosphonic acid, or a putativeurea-phosphonate complex.

TABLE 2 NMR Evidence for Guanidinium-Phosphate Binding. Half- ChemicalHeight Spectrum Content shift (ppm) Width (Hz) A, 4 equiv MePO₃K₂ + 4 eq9a 21.6 35.5 A, 2 equiv MePO₃K₂ + 2 eq 9a 21.6 20.0 A, 1 equiv MePO₃K₂ +1 eq 9a 22.4 11.2 A, 0 equiv MePO₃K₂ 21.4 4.2 B, 3 equiv MePO₃K₂ + 3 eqHCl 30.4 3.4 B, 2 equiv MePO₃K₂ + 2 eq HCl 29.9 3.4 B, 1 equiv MePO₃K₂ +1 eq HCl 27.8 3.8 B, 4 equiv MePO₃K₂ 21.4 4.2 C, 1 equiv MePO₃K₂ + 4 eq.NH₄Cl 22.1 4.2 C, 0 equiv MePO₃K₂ + 1 eq NH₄Cl 21.8 3.6 C, 0 equivMePO₃K₂ 21.4 4.2 D, 4 equiv MePO₃K₂ + 4 eq urea + 2 eq HCl 27.7 3.6 D, 1equiv MePO₃K₂ + 1 eq urea + 2 eq HCl 27.6 3.3 D, 0 equiv MePO₃K₂ 21.44.24. Bi-Directional Functionalization of Fluorinated Diols

The methods developed above for the synthesis of fluorinated amphiphilesalso have utility in bidirectional applications. Our general route todoubly functionalized fluorinated materials is sketched in Table 3.Thus, treatment of diols such as compound 21 withtrifluoromethanesulfonyl chloride gives easy access to bis(sulfonic)esters 30, which are remarkably stable and easily manipulated buildingblocks. Entries 1-5 of Table 3 illustrate conditions for the doubledisplacement of triflate 30. Since dehydrofluorination is facile in manyfluorous compounds in the presence of stronger bases, only weakly basicnucleophiles were used here. For example, bromide can displace thetriflate easily to give compound 31a in 81% yield. Treatment of compound30 with potassium malonate results in selective cyclization to giveocta(fluoro)cycloheptane 31b. While fluorocarbon chains are known to bemore rigid than their hydrocarbon counterparts, the formation of thisseven-membered ring indicates that the octafluoro-precursor isreasonably flexible. We found C—N bond formation with compound 30 toproceed smoothly under multiple conditions: both phthalimide and azidereact with compound 30 to generate the respective intermediates 31c and31d in high yield (entries 3 and 4). Compound 31d forms with lessapparent degradation of the fluorocarbon group. Installation of anintermediate triflate in the synthesis of compound 31 d seems essential:attempts to obtain compound 31d directly using diphenylphosphoryl azideleft diol 21 unreacted. Direct hydrogenation of compound 31d using Pd/Cled to extensive degradation while little or no product was formed. Bycontrast, using the Lindlar catalyst afforded 32 with satisfying yieldin the presence of quinoline (entry 7). Compound 31 d participates indouble Hüisgen cycloaddition under traditional conditions in high yield(entry 8).

TABLE 3 Synthesis and Derivatization of Fluorinated Bis(sulfonic) Ester30. (See FIG. 7) Starting Nucleophile or Entry Material reagentConditions Product Yield^(a) 1 30  KBr DMF, 8-Crown-6, rt

31a 81% 2 30 

DMF, rt

31b 57% 3 30 

DMF, 85° C.

31c 89% 4 30  NaN₃ DMF, rt

31d >99%  5 6   7 31c 31d   31d H₂NNH₂ H₂   H₂ EtOH, 65° C. H₂(balloon), EtOH, Lindlar, rt H₂ (balloon), EtOH, Lindlar, quinoline, rt

32 76% 13%   59% 8 31d

DMF, CuI, 70° C.

33 85% ^(a)All yields are isolated yields.

SUMMARY

Triflate esters, which are easily prepared from the correspondingcommercially available diols, are effective building blocks for nitrogensubstituted fluorous-phase amphiphiles that are not easily preparedthrough other methods. These reactions are high yielding, operationallysimple, and afford easy access to highly fluorinated materials. Amongthese compounds, guanidine-terminated amphiphiles have special valuebecause they present an interesting approach to bindingphosphate-covered molecules or materials in aqueous solution. Ongoingresearch in our laboratories involves the application of these materialsto the control of nanoparticle solubility and self-assembly.

General Procedures: All water sensitive procedures were carried outusing standard Schlenk techniques under nitrogen when indicated. Allreagents were purchased from Alfa Aesar or TCI and used without furtherpurification. Dry solvents were obtained from EMD. All other solventswere reagent grade and used as received. Distilled water was purchasedfrom Arrowhead.

Deuterated NMR solvents were purchased from Cambridge Isotopes Labs.Chloroform-d (CDCl₃) was used as received; NMR spectra were obtained ona Varian Mercury 400, Varian VNMRS 500, or Varian VNMRS 600 MHzspectrometer. All chemical shifts are reported in units of ppm andreferenced to the residual ¹H solvent. Data are reported as follows:chemical shift (ppm); multiplicity (s: singlet, d: doublet, t: triplet,q: quartet, h: heptet, m: multiplet, br: broad, tm: triplet ofmultiplet, tq: triplet of quintet); integration; coupling constants(Hz); assignment. ¹³C NMR spectra were referenced to the solventchemical shift at 77.0 ppm for CDCl₃. ¹⁹F NMR spectra were referenced toCFCl₃ as an external standard at 0.0 ppm. All NMR spectra were taken at25° C. unless otherwise indicated.

Mass spectra were obtained by electrospray ionization (ESI). MALDI massspectra were obtained on an Applied Biosystems Voyager spectrometerusing the evaporated drop method on a coated 96 well plate. The2,5-dihydroxybenzoic acid from Aldrich was used as a matrix. In astandard preparation, ca. 1 mg of analyte and ca. 20 mg of matrix weredissolved in a 1 mL of suitable solvent and spotted on the plate with amicropipette.

PEG Tosylate 23

To a solution of tetraethyleneglycol monomethyl ether (22) (10.0 g, 48.0mmol) and pyridine (84 mL) in CH₂Cl₂ (DCM) (170 mL), solidp-toluenesulfonyl chloride (22.0 g, 115.4 mmol) was added portion-wiseat −20° C. under nitrogen. The resulting reaction mixture was stirredfor 2 days at −20° C. Then, the reaction mixture was allowed to warm toroom temperature and water (200 mL) was added. The aqueous layer wasextracted with CH₂Cl₂ (150 mL×3). The combined organic fractions weredried over MgSO₄ and the solvent was removed under reduced pressure. Thecrude product was purified by chromatography on silica (1:1EtOAc:hexanes; R_(f)=0.3) to yield compound 23 as a colorless oil, 16.4g, 94%. ¹H NMR (500 MHz, CDCl3): δ=7.80 (d, Ar, 2H), 7.34 (d, Ar, 2H),4.16 (t, 2H), 3.66 (t, 2H), 3.62-3.65 (m, 6H), 3.58 (s, 4H), 3.532-3.56(m, 2H), 3.34 (s, 3H), 2.43 (s, 3H). ¹³C NMR (125 MHz, CDCl₃): δ=144.71(s, CSO₂O), 132.94 (s, CH₃CCH), 129.74 (s, CHCHCSO₂), 127.89 (s, CCHCH),71.79, 70.57, 70.46, 70.44, 70.38, 70.36, 69.20, 68.52, 58.94 (CH₃OCH₂),21.56 (CH₃CHCH). This data is consistent with a previously reportedcompound.

PEG-Fluorinated Alcohol 24a

To a solution of diol 21 (10.85 g, 41.4 mmol) in dry dioxane (236 mL),NaH powder (0.563 g, 23.46 mmol) was added under nitrogen and stirredfor 30 min at room temperature. The reaction flask was then placed in90° C. oil bath and continued to stir for 2 hours. A solution ofcompound 23 (5 g, 13.8 mmol) in dry dioxane (20 ml) was then added dropwise. The mixture stirred overnight. Then the reaction was cooled downand quenched by hydrochloric acid (2 M in diethyl ether, 4.33 mL), andthe solvent was removed under reduced pressure. The crude compound wasdissolved in dichloromethane (200 mL) and a white precipitate wasremoved via filtration. After solvent removal, the crude product waspurified by flash chromatography (1:2 ethyl acetate:hexanes, R_(f)=0.5)to yield the monosubstituted product as a clear oil, 3.86 g, 62%. ¹H NMR(400 MHz, CDCl₃): δ=4.09-3.96 (m, 4H, OCH₂(CF₂)₄CH₂OH), 3.78-3.74 (m,2H), 3.67-3.61 (m, 12H), 3.55-3.52 (m, 2H), 3.36 (s, 3H, OCH₃), 3.12 (t,³J_(F,F)=7.2 Hz, 1H, CH₂OH). ¹³C NMR (125 MHz, CDCl₃): δ=118.08-109.06(m, CF₂), 72.37, 72.00, 70.80, 70.77, 70.67, 70.63, 70.53, 68.3 (t,²J_(C,F)=24.9 Hz, CF₂CH₂OCH₂), 60.59 (t, ²J_(C,F)=25.4 Hz, CF₂CH₂OH),59.07 (s, CH₃O). ¹⁹F NMR (376 MHz, CDCl3): δ=(−124.1)-(−124.1) (m, 4F),−123.0 (p, ³J_(F,F)=214.8 Hz, 2F), −120.4 (p, ³J_(F,F)=13.3 Hz, 2F).FT-IR (cm⁻¹, neat): v=3415, 2882, 1457, 1351, 1177-1119, 946, 865, 762.MALDI-TOF for C₁₅H₂₄F₈O₆ [MNa]⁺: calculated 475.13 g/mol. found 475.10g/mol.

PEG-Fluorinated Alcohol 24b, 24c

Compounds 24b and 24c were prepared in the same way as compound 24a with51% and 60% yield, respectively. Compound 24b. ¹H NMR (400 MHz, CDCl₃):δ=4.07 (td, ³J_(H,F)=15.32 Hz, ³J_(H,H)=7.3, 4H, HOCH₂(CF₂)₃), 4.00 (t,³J_(H,F)=14.3 Hz, 4H, HOCH₂(CF₂)₃CH₂), 3.77-3.76 (m, 2H), 3.68-3.63 (m,12H), 3.56-3.54 (m, 2H), 3.38 (s, 3H, OCH₃), 2.91 (t, ³J_(H,H)=7.3 Hz,1H, CH₂OH). ¹³C NMR (126 MHz, CDCl₃): δ=118.19-109.41 (m, (CF₂)₃),72.06, 71.94, 70.66-70.48 ((OCH₂CH₂O)₄), 68.20 (t, ²J_(C,F)=25.4 Hz,CF₂CH₂OCH₂), 60.31 (t, ²J_(C,F)=25.4 Hz, CF₂CH₂OH), 59.01 (s, CH₃O). ¹⁹FNMR (376 MHz, CDCl3): δ=−120.46 (m, 2F), −123.05 (m, 2F), −127.47 (m,2F). FT-IR (cm⁻¹, neat): v=3421, 2881, 1460, 1350, 1285-1307, 937, 886,850, 771, 668. MALDI-TOF for C₁₄H₂₄F₆O₆ [MNa]⁺: 425.14 g/mol, found425.03 g/mol. Compound 24c. ¹H NMR (400 MHz, CDCl₃): δ=4.09 (td,³J_(H,F)=14.3 Hz, ³J_(H,H)=7.6, 4H, HOCH₂(CF₂)₆), 4.04 (t, ³J_(H,F)=14.2Hz, 4H, HOCH₂(CF₂)₆CH₂), 3.79-3.77 (m, 2H), 3.69-3.63 (m, 12H),3.56-3.54 (m, 2H), 3.38 (s, 3H, OCH₃), 2.19 (t, ³J_(H,H)=7.6 Hz, 1H,CH₂OH). ¹³C NMR (126 MHz, CDCl₃): δ=117.82-108.76 (m, (CF₂)₃), 72.41,72.00, 70.82-70.56 ((OCH₂CH₂O)₄), 68.44 (t, ²J_(C,F)=24.4 Hz,CF₂CH₂OCH₂), 60.60 (t, ²J_(C,F)=25.4 Hz, CF₂CH₂OH), 59.08 (s, CH₃O). ¹⁹FNMR (470 MHz, CDCl3): δ=−120.25 (m, 2F), −122.60 (m, 4F), −122.83 (m,2F), −124.08 (m, 4F). FT-IR (cm⁻¹, neat): v=3408, 2884, 1645, 1457,1197-1106, 944, 846, 758-726. MALDI-TOF for C₁₇H₂₄F₁₂O₆ [MNa]⁺: 575.13g/mol, found 575.08 g/mol.

PEG-Fluorinated Triflate 25a

To a solution of compound 24a (1 g, 2.21 mmol) in dry THF (3.3 mL),triethylamine (0.68 ml, 4.862 mmol) was added under N₂ atmosphere. Themixture was stirred for 10 min, after which the flask was cooled to 0°C. Trifluoromethanesulfonyl chloride (0.47 ml, 4.42 mmol) was then addedand the reaction mixture was stirred for 14 hours. The solvent wasremoved under reduced pressure. The crude product was dissolved in etherand filtered to remove a white solid. The solvent of the filtrate wasremoved under reduced pressure. The crude product was purified by flashchromatography (2:1 ethyl acetate:hexanes, R_(f)=0.42) to give compound25a as a clear, oily liquid (1.05 g). Yield: 81%, conversion: 95%. ¹HNMR (400 MHz, CDCl₃): δ=4.79 (t, ³J_(H,F)=12.6 Hz, 2H, CF₃SO₂OCH₂CF₂),4.01 (t, ³J_(H,F)=13.9 Hz, 2H, CH₂OCH₂CF₂), 3.77-3.73 (m, 2H), 3.66-3.59(m, 12H), 3.53-3.50 (m, 2H), 3.35 (s, 3H, CH₃O). ¹³C NMR (100 MHz,CDCl₃): δ=118.4 (q, ¹J_(C,F)=318.9 Hz, SO₂CF₃), 117.89-110.77 (m, CF₂),72.2, 71.8, 70.62, 70.59, 70.51, 70.49, 70.42, 68.45 (t, ²J_(C,F)=27.3Hz, CH₂OTf), 68.16 (t, ²J_(C,F)=24.9 Hz, CH₂OCH₂CF₂), 58.9 (s, CH₃O).¹⁹F NMR (376 MHz, CDCl₃): δ=−124.0 (m, 4F), −120.5 (p, 2F, ²J_(C,F)=12.4Hz, OCH₂CF₂), −120.3 (m, 2F, CF₂CH₂OTf), −74.6 (s, 3F, CF₃SO₂). FT-IR(cm⁻¹, neat): v=2885, 1428, 1215-1134, 1017, 958, 838, 611. MALDI-TOFfor C₁₆H₂₃F₁₁O₈S [MNa]⁺: calculated 607.08 g/mol. found 606.85 g/mol.

PEG-Fluorinated Triflate 25b, 25c

Compounds 25b, 25c were prepared in a similar way as compound 25a toafford 60% yield (100% conversion) and 93% yield (95% conversion),respectively. Compound 5b: ¹H NMR (500 MHz, CDCl₃): δ=4.82 (t,³J_(H,F)=13.2 Hz, 2H, CF₃SO₂OCH₂CF₂), 4.03 (t, ³J_(H,F)=14.2 Hz, 2H,CH₂OCH₂CF₂), 3.77-3.76 (m, 2H), 3.67-3.63 (m, 12H), 3.55-3.53 (m, 2H),3.37 (s, 3H, CH₃O). ¹³C NMR (126 MHz, CDCl₃): δ=118.57 (q,¹J_(C,F)=318.6 Hz, SO₂CF₃), 117.4-108.8 (m, CF₂), 72.35, 72.07, 70.83,70.76, 70.74, 70.71, 70.65, 69.03 (t, ²J_(C,F)=26.4 Hz, CH₂OTf), 68.14(t, ²J_(C,F)=26.4 Hz, CH₂OCH₂CF₂), 58.9 (s, CH₃O). ¹⁹F NMR (470 MHz,CDCl₃): δ=(−123.9)-(−124.1) (m, 4F, CF₂CF₂CH₂), −120.5 (p, 2F,³J_(C,F)=12.4 Hz, OCH₂CF₂), (−120.2)-(−120.35) (m, 2F, CF₂CH₂OTf), −74.6(s, 3F, CF₃SO₂). FT-IR (cm⁻¹, neat): v=2878, 1427, 1216, 1144 1008, 969,613. MALDI-TOF for C₁₅H₂₃F₉O₈S [MNa]⁺: calculated 557.09 g/mol. found556.90 g/mol.

Compound 25c. ¹H NMR (500 MHz, CDCl₃): δ=4.80 (t, ³J_(H,F)=12.2 Hz, 2H,CF₃SO₂OCH₂CF₂), 4.02 (t, ³J_(H,F)=13.4 Hz, 2H, CH₂OCH₂CF₂), 3.77-3.75(m, 2H), 3.66-3.60 (m, 12H), 3.53-3.51 (m, 2H), 3.35 (s, 3H, CH₃O). ¹³CNMR (126 MHz, CDCl₃): δ=118.52 (q, ¹J_(C,F)=320.7 Hz, SO₂CF₃),118.03-108.41 (m, CF₂), 72.41, 72.02, 70.82-70.60, 68.37 (t,³J_(C,F)=28.9 Hz, CH₂OTf), 68.13 (t, ³J_(C,F)=28.9 Hz, CH₂OCH₂CF₂), 59.0(s, CH₃O). ¹⁹F NMR (470 MHz, CDCl₃): δ=−120.16 (m, 4F), −122.5 (m, 2F),−122.48 (m, 2F), −123.43 (m, 2F), −74.4 (s, 3F, CF₃SO₂). FT-IR (cm⁻¹,neat): v=2884, 1427, 1203, 1142, 1012, 956, 821, 612. MALDI-TOF forC₁₈H₂₃F₁₅O₈S [MNa]⁺: calculated 707.08 g/mol. found 706.73 g/mol.

PEG-Fluorinated Phthalimide 26

Potassium phthalimide (4.12 g, 22.3 mmol) was added to a solution ofcompound 25a (6.5 g, 11.1 mmol) in DMF (223 mL). The reaction wasstirred at 65° C. overnight under nitrogen. The reaction was then cooledto room temperature and solvent was removed under reduced pressure.Chloroform (200 mL) was added and a white precipitate was filtered. Thesolvent was removed under reduce pressure. The compound was thenpurified on a silica gel column with a solvent gradient (in 4:1 ethylacetate:hexanes R_(f)=0.4) to yield a clear oil 5.4 g, 84%. ¹H NMR (400MHz, CDCl₃): δ=7.92 (q, ³J_(H,H)=2.8 Hz, Ar, 4H), 7.78 (q, ³J_(H,H)=2.8Hz, Ar, 4H), 4.35 (t, ³J_(H,F)=15.8 Hz, 2H, NCH₂CF₂), 4.03 (t,³J_(H,F)=14.4 Hz, 2H, CH₂OCH₂CF₂), 3.80-3.75 (m, 2H), 3.69-3.61 (m,12H), 3.56-3.51 (m, 2H), 3.36 (s, 3H, CH₃O). ¹³C NMR (100 MHz, CDCl₃):δ=166.9 (s, Ar), 134.5 (s, Ar), 131.6 (s, Ar), 123.9 (s, Ar),118.4-109.2 (m, CF₂), 72.3, 71.9, 70.71, 70.67, 70.64, 70.58, 70.56,70.52, 70.48, 70.44, 68.3 (t, ²J_(C,F)=24.9 Hz, CF₂CH₂OCH₂), 58.97 (s,CH₃O), 37.45 (t, ²J_(C,F)=23.5 Hz, CF₂CH₂N). ¹⁹F NMR (376 MHz, CDCl₃):δ=−124.13 (m, 2F), −123.73 (m, 2F,), −120.35 (m, 2F), −116.6 (m, 2F).FT-IR (cm⁻¹, in CDCl₃): v=3154, 2985, 2903, 2254, 1793, 1472, 1378,1382, 1099, 910, 733. MALDI-TOF for C₂₃H₂₇F₈NO₇ [MNa]⁺: calculated604.1557 g/mol. found 603.8150 g/mol.

PEG-Fluorinated Amine 27a

Compound 26 (3.8 g, 6.5 mmol) was treated with hydrazine (2.05 mL, 65.2mmol) in anhydrous ethanol (150 mL) at 65° C. and stirred overnightunder nitrogen. The reaction was cooled to room temperature. Whiteprecipitate was filtered and washed with CHCl₃. The solvent was removedunder reduced pressure. Chloroform (200 mL) was then added and stirredfor 30 minutes. More white precipitate was obtained and the precipitatewas filtrated and the solvent was removed to yield the product as lightyellow oil, 2.74 g, 93%.

Alternative route to prepare compound 27a via a one-pot hydrogenation ofazide 28a: To a solution of 25a (190 mg, 0.33 mmol) in DMF (1.5 mL),sodium azide (26.6 mg, 0.41 mmol) was added under nitrogen. The reactionmixture was stirred for 6.5 hours. Then Pd/C (2.4 mg, 10% w/w) was addedand the reaction was purged under hydrogen gas. A balloon filled withhydrogen gas was attached to the reaction, which was then stirred for 3hrs. Then the Pd/C was filtered out on a pad of Celite. The reactionmixture was poured over 1M aqueous HCl (2 mL) and, washed with ether(1.5 mL×2). The pH of the aqueous phase was adjusted to 12 withsaturated NaOH solution, and extracted with ether (2 mL×3). The combinedorganic fractions were dried over MgSO₄. The solvent was removed underreduced pressure to afford compound 27a as a yellow, oily liquid (102.8mg). Yield: 70%. Compound 27a. ¹H NMR (400 MHz, CDCl₃): δ 4.02 (t,³J_(H,F)=14.3 Hz, 2H, CH₂OCH₂CF₂), 3.80-3.75 (m, 2H), 3.69-3.61 (m,12H), 3.56-3.51 (m, 2H), 3.37 (s, 3H, CH₃O), 3.24 (t, ³J_(H,F)=15.8 Hz,2H, NCH₂CF₂), 1.36-1.21 (br, 2H, CF₂CH₂NH₂). ¹³C NMR (100 MHz, CDCl₃):δ=118.4-109.6 (m, CF₂), 72.3, 71.9, 70.71, 70.68, 70.65, 70.59, 70.57,70.50, 68.3 (t, ³J_(C,F)=24.6 Hz, CF₂CH₂OCH₂), 58.99 (s, CH₃O), 42.92(t, ³J_(C,F)=24.1 Hz, CF₂CH₂NH₂). ¹⁹F NMR (376 MHz, CDCl₃): δ=−124.5 (m,2F), −124.21 (m, 2F), −122.17 (m, 2F), −120.50 (m, 2F). FT-IR (cm⁻¹, inCDCl₃): v=3409, 3340, 2878, 1632, 1460, 1352, 1232-1115, 956, 858.MALDI-TOF for C₁₅H₂₅F₈NO₅ [MH]⁺, calculated 452.17 g/mol. found 451.96g/mol.

PEG-Fluorinated Amines 27b, 27c

Compound 27c was prepared in the same way as compound 7a via one-pothydrogenation of the corresponding azide, and was isolated as a yellowoil in 65% yield. 7b was prepared from the azide precursor 28b, whichwas first purified and subjected to two different conditions forhydrogenation. Both conditions gave the product as a clear oil. UsingEtOH as a solvent gave compound 27b with 68% yield. Using DMF as asolvent gave compound 27b with 72% yield. Compound 27b. ¹H NMR (500 MHz,CDCl₃): δ 3.99 (t, ³J_(H,F)=14.3 Hz, 2H, CH₂OCH₂CF₂), 3.78-3.76 (m, 2H),3.70-3.63 (m, 12H), 3.56-3.54 (m, 2H), 3.39 (s, 3H, CH₃O), 3.31 (t,³J_(H,F)=15.3 Hz, 2H, NCH₂CF₂), 1.56 (br, 2H, CF₂CH₂NH₂). ¹³C NMR (126MHz, CDCl₃): δ=120.26-109.56 (m, CF₂), 72.34, 72.02, 70.79-70.60, 68.36(t, ²J_(C,F)=24.5 Hz, CF₂CH₂OCH₂), 59.08 (s, CH₃O), 43.05 (t,³J_(C,F)=24.6 Hz, CF₂CH₂NH₂). ¹⁹F NMR (470 MHz, CDCl₃): δ=−119.84 (m,2F), −121.62 (m, 2F,), −122.04 −122.01 (m, 2F), −122.15 (m, 2F), −123.56(m, 2F), −123.70 (m, 2F). FT-IR (cm⁻¹, in CHCl₃): v=3408, 3340, 2875,1632, 1456, 1350, 1284, 1234, 1141, 956, 881. MALDI-TOF for C₁₄H₂₅F₆NP₅[MH]⁺: calculated 402.17 g/mol. found 402.04 g/mol. Compound 27c. ¹H NMR(500 MHz, CDCl₃): δ 4.02 (t, ³J_(H,F)=14.0 Hz, 2H, CH₂OCH₂CF₂),3.77-3.75 (m, 2H), 3.66-3.61 (m, 12H), 3.53-3.52 (m, 2H), 3.36 (s, 3H,CH₃O), 3.24 (t, ³J_(FLF)=15.8 Hz, 2H, NCH₂CF₂), 1.28 (br, 2H,CF₂CH₂NH₂). ¹³C NMR (126 MHz, CDCl₃): δ=118.78-108.75 (m, CF₂), 72.43,72.03, 70.83-70.58, 68.43 (t, ²J_(C,F)=25.43 Hz, CF₂CH₂OCH₂), 59.08 (s,CH₃O), 42.96 (t, ³J_(C,F)=23.5 Hz, CF₂CH₂NH₂). ¹⁹F NMR (470 MHz, CDCl₃):δ=−119.84 (m, 2F), −121.62 (m, 2F,), −122.04 −122.01 (m, 2F), −122.15(m, 2F), −123.56 (m, 2F), −123.70 (m, 2F). FT-IR (cm⁻¹, in CHCl₃):v=3411, 3348, 2881, 1632, 1458, 1351, 1200-1141, 960, 840. MALDI-TOF forC₁₇H₂₅F₁₂NP₅ [MNa]⁺: calculated 574.14 g/mol. found 574.12 g/mol.

PEG-Fluorinated Azide 28a

To a solution of compound 25a (194 mg, 0.34 mmol) in DMF (1.5 mL),sodium azide (26.7 mg, 0.41 mmol) was added under nitrogen. The reactionmixture was stirred for 6.5 hours. The reaction mixture was poured overH₂O (2 mL) and extracted with Et₂O (2 mL×3). The combined organicfraction was washed with H₂O (6 mL×3) and dried over MgSO₄. The solventwas removed under reduced pressure to obtain compound 28a as alight-yellow liquid (136 mg, 84%). ¹H NMR (500 MHz, CDCl₃): δ 4.02 (t,³J_(H,F)=14.3 Hz, 2H, CH₂OCH₂CF₂), 3.79-3.77 (m, 2H), 3.75 (t,³J_(H,F)=14.6 Hz, 2H, N₃CH₂CF₂), 3.68-3.63 (m, 12H), 3.55-3.53 (m, 2H),3.38 (s, 3H, CH₃O). ¹³C NMR (125 MHz, CDCl₃): δ=117.97-108.79 (m, CH₂),72.38, 72.00, 70.79, 70.75, 70.68, 70.66, 70.58, 68.38 (t, ³J_(C,F)=24.6Hz, CF₂CH₂OCH₂), 59.04 (s, CH₃O), 50.18 (t, ³J_(C,F)=23.9 Hz, CH₂N₃).¹⁹F NMR (470 MHz, CDCl₃): δ=−118.08 (m, 2F), −120.32 (m, 2F), −123.95(m, 2F), −124.11 (m, 2F). FT-IR (cm⁻¹, in CDCl₃): v=2881, 2113, 1456,1123, 960, 857. MALDI-TOF for C₁₅H₂₄F₈N₃O₅ [MH]⁺, calculated 478.16g/mol. found 478.02 g/mol.

PEG-Fluorinated Azide 28b, 28c

Compounds 28b,28c were prepared in a similar way as 28a to afford >99%and 87% as yields, respectively. Compound 28b. ¹H NMR (500 MHz, CDCl₃):δ 4.01 (t, ³J_(H,F)=14.4 Hz, 2H, CH₂OCH₂CF₂), 3.78-3.75 (m, 2H), 3.77(t, ³J_(H,F)=14.6 Hz, 2H, N₃CH₂CF₂), 3.68-3.63 (m, 12H), 3.55-3.53 (m,2H), 3.37 (s, 3H, CH₃O). ¹³C NMR (125 MHz, CDCl₃): δ=117.97-108.58 (m,CH₂), 72.13, 71.84, 70.68, 70.60, 70.54, 70.51, 70.49, 70.41, 68.04 (t,³J_(C,F)=24.9 Hz, CF₂CH₂OCH₂), 58.83 (s, CH₃O), 50.06 (t, ³J_(C,F)=23.5Hz, CH₂N₃). ¹⁹F NMR (470 MHz, CDCl₃): δ=−118.30 (m, 2F), −120.21 (m,2F), −126.43 (m, 2F). FT-IR (cm⁻¹, in CDCl₃): v=2881, 2114, 1653, 1457,1306, 1148, 956. MALDI-TOF for C₁₄H₂₄F₆N₃O₅ [MH]⁺, calculated 428.1620g/mol. found 428.1664 g/mol. Compound 28c. ¹H NMR (500 MHz, CDCl₃): δ4.04 (t, ³J_(H,F)=14.0 Hz, 2H, CH₂OCH₂CF₂), 3.80-3.77 (m, 2H), 3.77 (t,³J_(H,F)=15.6 Hz, 2H, N₃CH₂CF₂), 3.68-3.63 (m, 12H), 3.56-3.54 (m, 2H),3.38 (s, 3H, CH₃O). ¹³C NMR (125 MHz, CDCl₃): δ=117.97-108.58 (m, CH₂),72.13, 71.84, 70.68, 70.60, 70.54, 70.51, 70.49, 70.41, 68.04 (t,³J_(C,F)=24.9 Hz, CF₂CH₂OCH₂), 58.83 (s, CH₃O), 50.06 (t, ³J_(C,F)=23.5Hz, CH₂N₃). ¹⁹F NMR (470 MHz, CDCl₃): δ=−117.88 (m, 2F), −120.19 (m,2F), −122.30 (m, 2F), −122.50 (m, 2F), −123.66 (m, 2F), −123.88 (m, 2F).FT-IR (cm⁻¹, in CDCl₃): v=2881, 2114, 1456, 1142, 958. MALDI-TOF forC₁₇H₂₄F₁₂N₃O₅ [MH]⁺, calculated 578.1524 g/mol. found 577.9730 g/mol.

PEG-Fluorinated-Guanyldinium Mono TFA Salt 29b

To a solution of compound 27b (161.6 mg, 0.4 mmol) in DMF (0.4 mL),Hünig's base (0.14 mL, 0.8 mmol) and 1H-pyrazole-1-carboxamidinehydrochloride (117.3 mg, 0.8 mmol) were added and the reaction wasstirred vigorously. Another addition of Hünig's base and1H-pyrazole-1-carboxamidine hydrochloride was made at 72 hours. Anotheraliquot of Hünig's base and 1H-pyrazole-; 11-carboxamidine hydrochloridewas added at 6 days and every 24 hours thereafter to drive the reactionto completion. NMR and MALDI confirmed the completion of the reaction at11 days. The solvent was removed under reduced pressure. The crudeproduct was obtained as a yellow gum, which was then suspended in H₂Oand passed through an IRN-78 ion-exchange column to neutralize thehydrochloride. The resulting crude product was separated with reversephase chromatography (MeOH/H₂O, 0.1% TFA) to afford a light yellow oilas the product in mono-TFA salt form (126.8 mg, 57%). Compound 29b. ¹HNMR (500 MHz, 55° C., CDCl₃): δ8.62 (br, 1H, H₂NCNHNH₂), 7.37 (br, 4H,H₂NCNHNH₂), 3.96 (t, ³J_(H,F)=13.4 Hz, 2H, CH₂OCH₂CF₂), 3.92 (NHCH₂CF₂),3.77-3.75 (m, 2H), 3.65-3.62 (m, 12H), 3.55-3.53 (m, 2H), 3.34 (s, 3H,CH₃O). ¹³C NMR (126 MHz, CDCl₃): δ=158.9 (s, C═N), 117.9-109.2 (m,CF₂CF₂CF₂), 72.3, 71.8, 70.5-70.2, 68.2 (t, ²J_(C,F)=26.0 Hz,CF₂CH₂OCH₂), 58.7 (s, CH₃O), 42.1 (t, ²J_(C,F)=22.1 Hz, CF₂CH₂NH₂). ¹⁹FNMR (470 MHz, CDCl₃): δ=−75.78 (s, 3F, HOOCCF₃), −117.86 (m, 2F),−119.32 (m, 2F), −127.35 (m, 2F). FT-IR (cm⁻¹, in CHCl₃): v=3354-3015,2921, 1684, 1457, 1204, 1150-1136, 755. MALDI-TOF for C₁₅H₂₇F₆N₃O₅[MH]⁺: calculated 444.19 g/mol. found 444.07 g/mol.

PEG-Fluorinated-Guanyldinium Mono TFA Salts 29a and 29c

Compounds 29a and 29c were prepared in a way similar to 29b to give thecorresponding mono TFA salt product with 92% and 56% yields,respectively. Both 29a and 29c are light yellow oil. Compound 29a. ¹HNMR (500 MHz, 55° C., CDCl₃): δ8.28 (br, 1H, H₂NCNHNH₂), 7.34 (br, 4H,H₂NCNHNH₂), 3.97 (t, ³J_(H,F)=14.0 Hz, 2H, CH₂OCH₂CF₂), 3.93 (NHCH₂CF₂),3.74-3.73 (m, 2H), 3.66-3.60 (m, 12H), 3.54-3.52 (m, 2H), 3.33 (s, 3H,CH₃O). ¹³C NMR (126 MHz, CDCl₃): δ=158.72 (s, C═N), 117.82-108.96 (m,CF₂CF₂CF₂CF₂), 72.21, 71.78, 70.50-70.13, 68.24 (t, ²J_(C,F)=24.3 Hz,CF₂CH₂OCH₂), 58.55 (s, CH₃O), 41.84 (t, ²J_(C,F)=23.54 Hz, CF₂CH₂NH₂).¹⁹F NMR (376 MHz, CDCl₃): δ=−75.98 (s, 3F, HOOCCF₃), −117.81 (m, 2F),−119.72 (m, 2F), −123.55 (m, 2F), −123.58 (m, 2F,). FT-IR (cm⁻¹, inCHCl₃): v=3356-3014, 2920, 1684, 1457, 1177, 1132, 759. MALDI-TOF forC₁₆H₂₇F₈N₃O₅ [MNa]⁺: calculated 494.19 g/mol. found 494.06 g/mol.Compound 29c. ¹H NMR (500 MHz, 55° C., CDCl₃): δ8.34 (br, 1H, HOOCCF₃),7.41 (br, 4H, H₂NCNHNH₂), 3.97 (t, ³J_(H,F)=13.4 Hz, 2H, CH₂OCH₂CF₂),3.93 (NHCH₂CF₂), 3.75-3.73 (m, 2H), 3.65-3.59 (m, 12H), 3.53-3.51 (m,2H), 3.33 (s, 3H, CH₃O). ¹³C NMR (126 MHz, 55° C., CDCl₃): δ=158.88 (s,C═N), 118.15-108.56 (m, CF₂CF₂CF₂CF₂CF₂CF₂), 72.31, 71.86, 70.61-70.26,68.33 (t, ²J_(C,F)=24.4 Hz, CF₂CH₂OCH₂), 58.60 (s, CH₃O), 41.75 (t,²J_(C,F)=25.16 Hz, CF₂CH₂NH₂). ¹⁹F NMR (470 MHz, 55° C., CDCl₃):δ=−76.07 (S, SCF₃), −117.875 (m, 2F), −119.74 (m, 2F), −121.81 (m, 2F),−122.02 (m, 2F), −123.22 (m, 2F), −123.57 (m, 2F). FT-IR (cm⁻¹, inCHCl₃): v=3360-3184, 3020, 2904, 1684, 1216-1144, 761. MALDI-TOF forC₁₈H₂₇F₁₂N₃O₅ [MH]⁺: calculated 594.18 g/mol. found 593.99 g/mol.

Triflate 10

To a solution of diol 21 (5.0 g, 19.1 mmol) in dry dichloromethane (200mL), trifluoromethanesulfonyl chloride (4.9 mL, 45.8 mmol) was addedunder a nitrogen atmosphere in an ice bath. Triethylamine (10.7 mL, 76.3mmol) was then added dropwise. A yellow precipitate was observed. Themixture was stirred at room temperature overnight. The solvent was thenremoved and the crude compound was dissolved in ethyl acetate (200 mL)and washed twice with water (100 mL). The phases were separated, and theorganic phase was washed sequentially with 1M HCl (200 mL), NaHCO₃ (200mL), and brine and then dried with MgSO₄ and filtered. The solvent wasremoved under reduced pressure to yield a yellow oil. It was thencrystallized from 3:1 hexanes:ethyl acetate to yield compound 28 asclear crystals (9.4 g, 94%). mp. 57.5-58.5° C. ¹H NMR (400 MHz, CDCl₃):δ=4.82 (t, ³J_(H,F)=12.1 Hz, 4H, CF₃SO₂OCH₂CF₂). ¹³C NMR (150 MHz,CDCl₃): δ=118.42 (q, ¹J_(C,F)=320.1 Hz, CF₃SO₂), 115.5 (t, CF₂),113.6-112.6 (m, CF₂), 111.3-109.9 (m, CF₂), 108.0 (t, ²J_(C,F)=32.9 Hz,CF₂), 68.07 (t, ²J_(C,F)=28.4 Hz, OCH₂). ¹⁹F NMR (376 MHz, CDCl₃):δ=−123.35 (m, 4F, CF₂CF₂CH₂), −120.1 (m, 4F, CF₂CH₂O), −74.3 (s, 6F,CF₃SO₂). FT-IR (cm⁻¹, in CHCl₃): v=3683, 3020, 2400, 1519, 1429, 1220,931, 761. Anal. Calc'd for C₈H₄F₁₄O₄S₂: C, 18.26; H, 0.77. Found: C,19.87; H, 0.77.

Dibromide 31a

To a solution of compound 30 (100 mg, 0.18 mmol) in DMF (1.2 mL),potassium bromide (50.8 mg, 0.43 mmol) and 18-crown-6 (14.6 mg, 0.054mmol) were added under N₂ atmosphere. After 6 hours of stirring, KBr (25mg) was added and the reaction was allowed to continue for another 26hours. The reaction mixture was poured over H₂O (3.6 mL), extracted withether (2.4 mL×3), washed with H₂O (7.2 mL×3) and dried over MgSO₄.Solvent was removed under reduced pressure to afford the compound 23a asa clear oil (56.1 mg, 81%). ¹H NMR (500 MHz, CDCl₃): δ=3.76 (t,³J_(H,F)=15.6 Hz, 4H, BrCH₂CF₂). ¹³C NMR (126 MHz, CDCl₃): δ=113.99 (tt,¹J_(C,F)=257.25 Hz, ²J_(C,F)=31.8 Hz, CH₂CF₂), 110.91 (tq¹J_(C,F)=268.01 Hz, ²J_(C,F)=31.3 Hz, CH₂CF₂CF₂), 26.05 (t,²J_(C,F)=25.4 Hz, BrCH₂). ¹⁹F NMR (470 MHz, CDCl₃): δ=−113.10 (m, 4F,CF₂CF₂CH₂), −122.03 (m, 4F, CF₂CF₂CH₂). FT-IR (cm⁻¹, in CHCl₃): v=2987,2961, 2932, 1727, 1428, 1287-1072, 875. GC/MS for C₆H₄Br₂F₈ [M]⁺:calculated 385.8552 g/mol. found 385.8544 g/mol.

Malonocycloheptane 31b

In a 3-neck round bottom flask, potassium hydride (26.8 mg, 0.67 mmol,in mineral oil) was washed with pentane. DMF (1.8 mL) was then added. Tothis suspension of KH in DMF under vigorous stirring, dimethylmalonate(88.2 mg, 0.67 mmol) was added slowly. After 1 hour, compound 30 (150mg, 0.27 mmol) was added to the resulting enolate and the reaction wasstirred for 12 hours. After that, another aliquot of enolate was added,and the reaction was allowed to stir for 24 hours longer. The reactionmixture was poured over H₂O (3.6 mL) and extracted with ether (3.6mL×3). The combined organic fractions were washed with H₂O (9 mL×3) anddried over MgSO₄. The solvent was removed under reduced pressure. Thecrude product was purified by chromatography (7:1 benzene:ethyl acetate,R_(f)=0.74) to separate unreacted starting material, then furtherpurified by a second chromatography (4:1 hexanes:ethyl acetate,R_(f)=0.59) to obtain a clear liquid, which crystallized on standing.The crystal sublimes at room temperature. Yield: 54.3 mg, 57%, mp.67.5-69° C. ¹H NMR (400 MHz, CDCl₃): δ=3.83 (s, 6H, CH₃COC), 3.20 (t,³J_(H,F)=15.1 Hz, 4H, CCH₂CF₂). ¹³C NMR (126 MHz, CDCl₃): δ=168.42 (s,CH₃COC), 117.78-113.72 (tt, ¹J_(C,F)=254.4 Hz, ²J_(C,F)=27.9 Hz,CH₂CF₂), 111.38-107.08 (tq, ¹J_(C,F)=229.8 Hz, ²J_(C,F)=27.8 Hz,CH₂CF₂CF₂), 54.44 (s, CH₃CO), 33.02 (t, ²J_(C,F)=24.7 Hz, CH₂CF₂. ¹⁹FNMR (470 MHz, CDCl₃): δ=−111.41 (m, 4F, CF₂CF₂CH₂), −120.1 (m, 4F,CF₂CH₂O), −74.3 (s, 6F, CF₃SO₂). FT-IR (cm⁻¹, in CHCl₃): v=3021, 2958,1748, 1438, 1345, 1282, 1216, 1180, 1117, 1076, 1016, 932, 756, 668.GC/MS for C₁₀H₇F₈O₃ [M-OMe]⁺ calculated 327.03. found 327.08 g/mol;C₉H₇F₈O₂ [M-CO₂Me]⁺ calculated 299.03. found 299.08 g/mol.

Phthalimide 31c

To a solution of compound 30 (3.0 g, 5.7 mmol) in dryN,N-dimethylformamide (300 mL), potassium phthalimide (2.53 g, 13.7mmol) was added under nitrogen atmosphere. The mixture was stirred at85° C. overnight. The reaction mixture was cooled down to roomtemperature and 300 mL of brine was added. The product precipitated as awhite solid and was collected by filtration (2.6 g, 89%). Decomp. tempand mp. 260.5-262° C. ¹H NMR (400 MHz, CDCl₃): δ=7.93 (q, ³J_(H,H)=2.8Hz, Ar, 4H), 7.78 (q, ³J_(H,H)=2.8 Hz, Ar, 4H), 4.38 (t, ³J_(H,F)=15.6Hz, 4H, NCH₂CF₂). ¹³C NMR (100 MHz, CDCl₃): δ=166.8 (s, Ar), 134.5 (s,Ar), 131.8 (s, Ar), 123.9 (s, Ar), 37.6 (t, ³J_(C,F)=25.1 Hz, NCH₂). ¹⁹FNMR (376 MHz, CDCl₃): δ=−123.5-−123.6 (m, 4F, CF₂CF₂CH₂),−116.4-−(116.6) (m, 4F, CF₂CH₂N). Anal. Calc'd for C₁₃H₁₃O₄N: C, 50.78;H, 2.32; N, 5.38. Found: C, 50.73; H, 2.03; 5.05. FT-IR (cm⁻¹, inCHCl₃): v=3019, 2400, 1522, 1424, 1216, 930, 759. This data isconsistent with a previously-reported compound.

Azide 31d

To a solution of compound 30 (150 mg, 0.267 mmol) in DMF (1.8 mL), NaN₃(41.6 mg, 0.64 mmol) was added under N₂ atmosphere. The reaction wasstirred for 3 hours. The reaction mixture was then poured over of H₂O(3.6 mL) and extracted with ether (3.6 mL×3). The combined organicfractions were then washed with H₂O (10 mL×3) and dried over MgSO₄. Thesolvent was removed under reduced pressure to yield a colorless oil(83.3 mg, >99%). ¹H NMR (500 MHz, CDCl₃): δ=3.77 (t, ³J_(H,H)=14.7 Hz,4H, CH₂CF₂CF₂). ¹³C NMR (150 MHz, CDCl₃): δ=115.73 (tt, ¹J_(C,F)=258.9Hz, ²J_(C,F)=30.1 Hz, N₃CH₂CF₂), 111.82 (tq, ¹J_(C,F)=265.87 Hz,²J_(C,F)=33.52 Hz, NH₂CH₂CF₂CF₂), 50.20 (t, ²J_(C,F)=24.3 Hz, CH₂N₃).This data is consistent with a previously-reported compound.

Diamine 32 Via Phthalate Deprotection

Compound 31c (2.3 g, 4.4 mmol) was treated with hydrazine (1.4 mL, 44.4mmol) in anhydrous ethanol (300 mL) under reflux overnight. Aftercooling to room temperature, the reaction mixture was filtered to removethe white precipitate. The solvent was then removed under vacuum. Thecrude product was then stirred in 200 mL chloroform and re-filtered toremove white precipitate. Chloroform was removed by rotary evaporation,and the product was obtained as a white solid. It was sublimated toobtain clear crystals, 0.87 g, 76%. Mp. 47-48° C. ¹H NMR (400 MHz,CDCl₃): δ=3.24 (t, ³J_(H,H)=16.0 Hz, 4H, CH₂CF₂CF₂), 1.35-1.18 (b, 4H,NH₂CH₂CF₂). ¹³C NMR (150 MHz, CDCl₃): δ=118.4-117.8 (m, CF₂),116.5-116.1 (m, CF₂), 114.6 (t, ³J_(C,F)=28.5 Hz, CF₂), 113.4 (t,³J_(C,F)=35.1 Hz, CF₂), 111.7 (q, ³J_(C,F)=35.1 Hz, CF₂), 109.9 (t,³J_(C,F)=35.1 Hz, CF₂), 42.9 (t, ³J_(C,F)=24.6 Hz, CH₂NH₂). ¹⁹F NMR (376MHz, CDCl₃): δ=(−124.2)-(−124.4) (m, 4F, CF₂CF₂CH₂), (−122.1)−(−122.3)(m, 4F, CF₂CH₂NH₂). FT-IR (cm⁻¹, in CHCl₃): v=3020, 1215, 756. This datais consistent with a previously-reported compound.

Compound 32 can also be prepared via direct hydrogenation using thefollowing procedure:

To a solution of compound 31d (53 mg, 0.17 mmol) and quinoline (0.8 mg)in EtOH (0.85 mL), Lindlar (2.6 mg) was added under nitrogen. A balloonfilled with H₂ was immediately attached to the reaction. After 6 hr 45min of stirring, the balloon was removed and the reaction mixture wasfiltered over a pad of Celite. It was then poured over 1 mL of HCl andextracted with ether (2 mL×1). After adjusting the pH to 13 withsaturated NaOH solution, the aqueous phase was extracted with ether (2mL×3) and dried over MgSO₄. The crude product was separated usingflash-chromatography (chloroform:MeOH=1:12, R_(f)=0.33) to give compound32 as a clear crystal which sublimes at room temperature. 26.2 mg,Yield: 59%.

Triazole 33

To a solution of compound 31d (100 mg, 0.32 mmol) in DMF (1 mL),phenylacetylene (78.4 mg, 0.768 mmol), and CuI (9.1 mg, 0.048 mmol) wereadded sequentially. The reaction was heated at 70° C. for 12 hours. Thesolution was cooled and the solvent was removed under reduced pressure.The greenish crude product was then re-dissolved in a minimal amount ofacetone and passed through a plug of silica gel. The eluent wascollected and solvent was removed under reduced pressure to obtain ayellowish solid, which was then triturated with ethyl acetate andhexanes to obtain compound 33 as a white, fluffy solid, 147 mg, 89%. mp.242.5-245.5° C. ¹H NMR (599.804 MHz, DMSO): δ=8.74 (s, 1H, NCHC),7.91-7.90 (m, 2H, Ar, CHCHCH), 7.48-7.49 (m, 2H, Ar, CHCHCHN), 7.38-7.36(m, 1H, Ar, CHCHCH), 5.62 (t, 4H, ³J_(H,F)=15.9 Hz, 4H, CH₂CF₂CF₂). ¹³CNMR (150.837 MHz, DMSO): δ=146.79 (s, CCNCH), 130.02 (s, CHCC), 128.98(s, Ar, CHCHCH), 128.25 (s, Ar, CHCHCH), 125.34, (s, Ar, CHCHC), 123.50(s, CCHN), 116.3-112.9 (tm, ¹J_(C,F)=260.5, CF₂), 112.5-109.0 (tm,¹J_(C,F)=270.3, CF₂), 48.5 (t, ²J_(C,F)=22.5 Hz, CH₂N). ¹⁹F NMR (470MHz, DMSO): δ=−115.93 (m, 4F, CF₂CF₂CH₂), −122.43 (m, 4F, CF₂CH₂). FT-IR(cm⁻¹, in CH₂Cl₂): v=3052, 2988, 1419, 1265, 897, 737. MALDI-TOF forC₂₂H₁₇F₈N₆ [MH]⁺: calculated 517.14 g/mol. found 517.04 g/mol.

While exemplary embodiments are described above, it is not intended thatthese embodiments describe all possible forms of the invention. Rather,the words used in the specification are words of description rather thanlimitation, and it is understood that various changes may be madewithout departing from the spirit and scope of the invention.Additionally, the features of various implementing embodiments may becombined to form further embodiments of the invention.

What is claimed is:
 1. A method comprising: a) tosylating a compoundhaving formula 1 to form a compound having formula 2:

b) reacting a compound having formula (2) with a compound having formula(3) to form a compound having formula (4):

c) converting the hydroxyl group bonded to the carbon labeled “1” of thecompound having formula (4) to a leaving group to form a compound havingformula (5):

d) reacting the compound having formula (5) with a nucleophile to formthe compound having formula (6)

wherein: Le is a leaving group; R is a C₁₋₆ alkyl; m is an integer from3 to 7; n is an integer from 3 to 10; and Nu₁ is a portion of thenucleophile that bonds to the carbon atom labeled
 1. 2. The method ofclaim 1 wherein in step d) the compound having formula (4) is reactedwith trifluoromethanesulfonyl chloride to form a compound having formula(7):


3. The method of claim 1 wherein the nucleophile that is reacted withthe compound formula (5) has the following formula:

to form a compound having formula (9) has the following formula:


4. The method of claim 3 wherein the compound having formula (9) isconverted to a compound having formula (10):

or the amine protonated derivative thereof (10).
 5. The method of claim4 wherein the compound having formula (9) is reacted with hydrazine toform the compound having formula (10).
 6. The method of claim 5 whereinthe compound having formula (10) is converted to a compound havingformula (12):

or the imine protonated derivative thereof (12).
 7. The method of claim6 wherein the compound having formula (10) is reacted with a compoundhaving formula (13) to form the compound having formula (12):


8. The method of claim 1 wherein the compound having formula (5) isreacted with N₃ ⁻ in step d to form a compound having formula (11):


9. The method of claim 8 wherein the compound having (13) is convertedto the compound having formula (10):

or the amine protonated derivative thereof (10).
 10. The method of claim9 wherein the compound having formula (10) is converted to a compoundhaving formula (12):

or the imine protonated derivative thereof (12).
 11. The method of claim10 wherein the compound having formula (10) is reacted with a compoundhaving formula (13) to form the compound having formula (12):


12. The method of claim 7 or 11 wherein the compound having formula (12)is reacted with a compound having —PO₂OR₂ ⁻ or —CO₂ ⁻ groups to form acomplex having formula (15) or (16) respectively:

wherein R₁ is a C₈₋₃₀ hydrocarbon group, a functionalized C₈₋₃₀hydrocarbon group such that R₁ is fully saturated or includes 1 to 4carbon to carbon double bonds or 1 to 4 carbon to carbon triple bonds orcombinations thereof; R₂ is H, a C₈₋₃₀ hydrocarbon group, afunctionalized C₈₋₃₀ hydrocarbon group such that R₁ is fully saturatedor includes 1 to 4 carbon to carbon double bonds or 1 to 4 carbon tocarbon triple bonds; and R₃ and R₄ are each independently a C₈₋₃₀hydrocarbon group.
 13. The method of claim 12 wherein the complex havingformula (15) or formula (16) is part of a nanoparticle.
 14. The methodof claim 13 wherein the nanoparticle includes a paramagnetic atom. 15.The method of claim 14 wherein the paramagnetic atom is gadolinium(III).16. The method of claim 14 further comprising introducing thenanoparticle into a subject; separating the complex having formula (15)to expose the PO₃H⁻ groups; and imaging the paramagnetic atom bymagnetic resonance imaging.
 17. A complex having formula (15) or (16):

wherein: m is an integer from 3 to 7; and n is an integer from 3 to 10;R₁ is a C₈₋₃₀ hydrocarbon group, a functionalized C₈₋₃₀ hydrocarbongroup such that R₁ is fully saturated or includes 1 to 4 carbon tocarbon double bonds or 1 to 4 carbon to carbon triple bonds orcombinations thereof; R₂ is H, a C₈₋₃₀ hydrocarbon group, afunctionalized C₈₋₃₀ hydrocarbon group such that R₁ is fully saturatedor includes 1 to 4 carbon to carbon double bonds or 1 to 4 carbon tocarbon triple bonds; and R₃ and R₄ are each independently a C₈₋₃₀hydrocarbon group.